Numerous investigations indicate that the nucleus accumbens (Acb) is crucially involved in mediating the reinforcing actions of drugs of abuse such as cocaine and `natural' reinforcers such as food and water. We recently completed a series of studies that examined the activity of the same Acb neurons in rats responding on multiple schedules for either two distinct `natural' reinforcers (water and food), or one of those `natural' reinforcers and the intravenous self-administration of cocaine (Carelli et al., 2000; Appendix D). The results showed that the majority of neurons tested exhibited similar, overlapping neuronal firing patterns across the two `natural' reinforcer conditions. In contrast, the majority of neurons examined (> 90%) exhibited differential, nonoverlapping firing patterns relative to operant responding for water (or food) vs. cocaine reinforcement. Given these findings, four experiments are proposed in this application to provide critical information regarding factors that influence and/or control Acb reinforcement-related cell firing in behaving animals. Exp. 1 will determine the anatomic distribution of neurons in the Acb that selectively encode information related to water vs. cocaine reinforcement. This will be accomplished by the strategic positioning of microelectrodes into the core, shell and/or rostral pole of the Acb, and the specific `marking' of wires from which reinforcer selective cell firing was recorded during a water/cocaine multiple schedule. Exp. 2 will extend that study and determine if reinforcer selective cell firing is apparent during initial exposure to cocaine or if it is a direct consequence of repeated self-administration experience. Information gained in those studies will be expanded in Exps. 3 & 4 by determining the effects of interruption of drug access (abstinence) on cocaine selective cell firing. This is a critical issue since cocaine addiction in humans is typically characterized by periods of abstinence from drug taking and relapse (Gawin, 1991; O'Brien et al., 1992). Specifically, Exp. 3 will determine the firing properties of Acb neurons following various periods of cocaine abstinence (2, 4 and 8 weeks). Exp. 4 will determine the effects of cocaine abstinence on the associative properties of Acb cell firing documented in a number of published reports by the PI. Results of Exp. 4 will be directly relevant to understanding the biological basis of stimulus control in cocaine addiction reported to be a major contributor to problems in human drug abusers (O'Brien et al., 1992; Childress et al., 1999). Collectively, these studies will provide important insight into the functional organization of the Acb and its role in reinforcement-related processing in behaving animals.